Arylheteroaryl inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds which inhibit famesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting famesyl-protein transferase and the famesyl of the oncogene protein Ras.

This application claims the benefit of U.S. Provisional Application Nos.60/014,592 and 60/022,340 filed Apr. 3, 1996, and Jul. 24, 1996,respectively.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulation signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulation signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes famesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of famesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Famesyl-protein transferase utilizes famesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a famesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of famesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of famesyl-protein transferase (FPTase) have been describedin four general classes (S. Graham, Expert Opinion Ther. Patents, (1995)5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), whilea second class of inhibitors is related to the protein substrates (e.g.,Ras) for the enzyme. Bisubstrate inhibitors and inhibitors offarnesyl-protein transferase that are non-competitive with thesubstrates have also been described. The peptide derived inhibitors thathave been described are generally cysteine containing molecules that arerelated to the CAAX motif that is the signal for protein prenylation.(Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS,88:732-736 (1991)). Such inhibitors may inhibit protein prenylationwhile serving as alternate substrates for the famesyl-proteintransferase enzyme, or may be purely competitive inhibitors (U.S. Pat.No. 5,141,851, University of Texas; N. E. Kohl et al., Science,260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Ingeneral, deletion of the thiol from a CAAX derivative has been shown todramatically reduce the inhibitory potency of the compound. However, thethiol group potentially places limitations on the therapeuticapplication of FPTase inhibitors with respect to pharmacokinetics,pharmacodynamics and toxicity. Therefore, a functional replacement forthe thiol is desirable.

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It is, therefore, an object of this invention to develop low molecularweight compounds that will inhibit farnesyl-protein transferase andthus, the post-translational farnesylation of proteins. It is a furtherobject of this invention to develop chemotherapeutic compositionscontaining the compounds of this invention and methods for producing thecompounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises arylheteroaryl-containing compoundswhich inhibit the famesyl-protein transferase. Further contained in thisinvention are chemotherapeutic compositions containing these famesyltransferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formula A:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR2##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ and R² are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--;

R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ C(O)O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR3## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, Br, R¹¹O--, R¹¹ S(0)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle;

X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷ C(O)--,--C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --, provided that if a is N, then X isnot O, --C(O)NR⁷ --, --C(O)O--, --C(O)NR⁷ C(O)--, --S(O)₂ N(R¹⁰)--or--NR⁷ --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention is illustratedby the following formula A: ##STR4## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO,

e) ##STR5## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl;

X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--, --NR⁷--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰) S(O)₂ -- or --S(═O)_(m) --, provided thatif a is N, then X is not O, --C(O)NR⁷ --,--S(O)₂ N(R¹⁰)-- or --NR⁷ --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention areillustrated by the formula B: ##STR6## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

Another preferred embodiment of the compounds of this invention areillustrated by the formula C: ##STR7## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)R¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S (O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R⁶ c, R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ OC(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰OC(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰), R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰ --or O; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the inhibitors offamesyl-protein transferase are illustrated by the formula D: ##STR8##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(⁰)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --, or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl; R¹² isindependently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁-C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substitutedheteroaralkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--, provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰-- or O;

n is 0 or 1; provided n is not 0 if A¹ is a bond, O, --N(R¹⁰)--, orS(O)_(m) ;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In another more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula E:##STR9## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃-C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ peifluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

provided that if a is N, then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O;

n is 0 or 1;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰C(O)--, --NR¹⁰ -- or O;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offamesyl-protein transferase are illustrated by the formula F: ##STR10##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C 1-C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O or --C(═O)--;provided that if a is N, then X is not --C(O)NR¹⁰ -- or O;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula G: ##STR11##wherein: a is C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that atleast one of b, c, d or e is independently N, NH, O or S;

R¹ is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃-C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R² is independently selected from:

a) hydrogen,

b) aryl, heterocycle or C₃ -C₁₀ cycloalkyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R³ is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S (O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁴ is selected from H, halogen, CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;

provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a substitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

m is 0, 1 or 2; and

n is 0 or 1;

or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

1-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!ethyl}-4-phenyl-imidazole

1-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-4-phenylimidazole

1-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-4-(2-methyl)phenylimidazole

1-(3-Phenyl-5-isoxazolylmethyl)-5-(4-cyanobenzyl) imidazole

1-(3-Phenyl-isoxazol-5-ylacetyl)-5-(4-cyanobenzyl) imidazole

1-(4-Cyanobenzyl)-5-(4-Phenyl-thiazol-2-ylmethyl)imidazole

1-(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazole

1-(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2-ylmethyl)imidazole

1-(4-Cyanobenzyl)-5-(4-(naphth-2-yl)-thiazol-2-ylmethyl)imidazole

1-((4-(2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5-(4-cyanobenzyl)imidazole

1-((4-(2-methylphenyl)thiazole-2-ylethyl)-5-(4-cyanobenzyl) imidazole

or the pharmaceutically acceptable salts or optical isomers thereof.

Specific examples of the compounds of the invention are: ##STR12## orthe pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. Also, combinations of substituents/or variablesare permissible only if such combinations result in stable compounds.

As used herein, "alkyl" and the alkyl portion of aralkyl and similarterms, is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms; "alkoxy" represents an alkyl group of indicated number of carbonatoms attached through an oxygen bridge.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

"Alkynyl" groups include those groups having the specified number ofcarbon atoms and having one triple bonds. Examples of alkynyl groupsinclude acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl," and the aryl portion of aroyl and aralkyl, isintended to mean any stable monocyclic or bicyclic carbon ring of up to7 members in each ring, wherein at least one ring is aromatic. Examplesof such aryl elements include phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl,pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,thienofuryl, thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, andthienyl.

As used herein in the definition of R³, R⁴, R⁵ and R^(6a-e), the term"the substituted group" intended to mean a substituted C₁₋₈ alkyl,substituted C₂₋₈ alkenyl, substituted C₂₋₈ alkynyl, substituted aryl orsubstituted heterocycle from which the substituent(s) R³, R⁴, R⁵ andR^(6a-e) are selected.

As used herein in the definition of R⁷, the substituted C₁₋₈ alkyl,substituted C₃₋₆ cycloalkyl, substituted aroyl, substituted aryl,substituted heteroaroyl, substituted arylsulfonyl, substitutedheteroaryl-sulfonyl and substituted heterocycle include moietiescontaining from 1 to 3 substituents in addition to the point ofattachment to the rest of the compound.

As used herein, when no specific substituents are set forth, the terms"substituted aryl", "substituted heterocycle" and "substitutedcycloalkyl" are intended to include the cyclic group which issubstituted on a substitutable ring carbon atom with 1 or 2substitutents selected from the group which includes but is not limitedto F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--,--OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--,(C₁ -C₆ alkyl)C(O)--, (C₁ -C₆ alkyl)OC(O)--, N₃,(C₁ -C₆ alkyl)OC(O)NH--,phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl,furyl, isothiazolyl and C₁ -C₂₀ alkyl.

The moiety designated by the following structure ##STR13## represents anaromatic 5-membered heterocyclic ring and includes the following ringsystems: ##STR14## Preferably the aromatic 5-membered heterocyclic ringis selected from: ##STR15##

Lines drawn into the ring systems from substituents (such as from R³,R⁴, Q etc.) means that the indicated bond may be attached to any of thesubstitutable ring carbon or nitrogen atoms.

The substituent illustrated by the structure ##STR16## is a simplifiedrepresentation of a phenyl ring having five (5) substituents (hydrogensand/or non-hydrogens) and may also be represented by the structure##STR17##

The moiety described as ##STR18## where any two of R^(6a), R^(6b),R^(6c), R^(6d) and R^(6e) on adjacent carbon atoms are combined to forma diradical selected from --CH═CH--CH═CH, --CH═CH--CH--, --(CH₂)₄ -- and--(CH₂)₄ -- includes the following structures: ##STR19## It isunderstood that such fused ring moieties may be further substituted bythe remaining R^(6a), R^(6b), R^(6c), R^(6d) and/or R^(6e) as definedhereinabove.

Preferably, R¹ and R² are independently selected from: hydrogen, R¹¹C(O)O--, --N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ --, R¹⁰ -- or unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted phenyl,--N(R¹⁰)₂, R¹⁰ O-- and R¹⁰ C(O)NR¹⁰ --.

Preferably, R³ is selected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, CN, NO₂,R¹⁰ C(O)--or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --.

Preferably, R⁴ is selected from: hydrogen, halogen, trifluoromethyl,trifluoromethoxy and C₁ -C₆ alkyl.

Preferably, R⁵ is hydrogen.

Preferably, R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independentlyselected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, CN, NO₂, R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀cycloalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)-- or --N(R¹⁰)₂ ; or

any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --.

Preferably, R⁸ is independently selected from:

a) hydrogen, and

b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆perfluoroalkyl or CN. Preferably, R⁹ is hydrogen, halogen, CF₃ ormethyl. Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, n and r are independently 0, 1, or 2.

Preferably s is 0.

Preferably t is 1.

It is intended that the definition of any substituent or variable (e.g.,R^(1a), R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,--N(R¹⁰)₂ represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understoodthat substituents and substitution patterns on the compounds of theinstant invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be synthesizedby techniques known in the art, as well as those methods set forthbelow, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-25, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R³, R⁶ and R⁸,as shown in the Schemes, represent the substituents R³, R⁴, R⁵, R^(6a),R^(6b), R^(6c), R^(6d), R^(6e) and R⁸ ; although only one such R⁶ or R⁸is present in the intermediates and products of the schemes, it isunderstood that the reactions shown are also applicable when such arylor heteroaryl moieties contain multiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. Other reactions useful in the preparation of heteroarylmoieties are described in "Comprehensive Organic Chemistry, Volume 4:Heterocyclic Compounds" ed. P. G. Sammes, Oxford (1979) and referencestherein. Aryl-aryl coupling is generally described in "ComprehensiveOrganic Functional Group Transformations," Katritsky et al. eds., pp472-473, Pergamon Press (1995).

Synopsis of Schemes 1-25

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 1-15 illustrate synthesis of the instant arylheteroaryl compoundwhich incorporate a preferred benzylimidazolyl side-chain. Thus, inScheme 1, for example, a arylheteroaryl intermediate that is notcommercially available may be synthesized by methods known in the art.Thus, a phenyl boronic acid I may be reacted under Suzuki couplingconditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substitutedhalogenated heteroaryl moiety, such as 2-bromothienyl-4-carboxylic acid,to provide the arylheteroaryl carboxylic acid II. The acid may bereduced and the triflate of the intermediate alcohol III may be formedin situ and coupled to a suitably substituted benzylimidazolyl IV toprovide, after deprotection, the instant compound V.

Schemes 2-5 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 1.Thus, Scheme 2 illustrates the analogous s series of arylheteroarylalcohol forming reactions starting with the halogenatedheteroarylaldehyde.

Scheme 3 illustrates the reaction wherein the "terminal" phenyl moietyis employed in the Suzuki coupling as the halogenated reactant. Such acoupling reaction is also compatible when one of the reactantsincorporates a suitably protected hydroxyl functionality as illustratedin Scheme 4.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the arylheteroaryl component of the instant compounds, as shown inScheme 5. Thus, a zinc bromide adduct, such as phenyl zinc bromide, maybe coupled to a suitably substituted heteroaryl halide in the presenceof nickel (II) to provide the arylheteroaryl VI. The heteroaryl halide,phenyl halide and the zinc bromide adduct may be selected based on theavailability of the starting reagents.

As illustrated in Scheme 6, the sequence of coupling reactions may bemodified such that the aryl-heteroaryl bond is formed last. Thus, asuitably substituted imidazole may first be alkylated with aheteroarylmethyl halide to provide intermediate VII. Intermediate VIIcan then undergo Suzuki type coupling to a suitably substitutedheteroaryl boronic acid.

Scheme 7 illustrates the synthesis of a thiazole containing instantcompound from the acyclic precursors. Further substitution on thethiazole ring may be accomplished as illustrated in Scheme 7a. Similarstrategies may be utilized to prepare other bisheteroatom moieties.

Schemes 8 and 9 illustrate synthetic strategies that utilize thenucleophilicity of an imidazolyl moiety in the arylheteroaryl. Thus, asshown in Scheme 8, the commercially available 4-phenylimidazole may bereacted with a suitably substituted imidazolyl methyl halide to providethe instant compound VIII. If a particular substituted aryl imidazole isnot commercially available, it may be synthesized as illustrated inScheme 9.

Scheme 10 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 11 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the arylheteroaryl via an alkylamino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated arylheteroaryl moieties to provide the instantcompounds shown.

Compounds of the instant invention wherein the A¹ (CR¹ ₂)_(n) A² (CR¹₂)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 12. The suitably substituted phenol XIVmay be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 13 illustrates an analogous series of reactions wherein the (CR²₂)_(p) X(CR² ₂)_(p) linker of the instant compounds is oxygen. Thus, asuitably substituted haloheteroaryl alcohol, such as 4-bromo-2-thienol,is reacted with methyl N-(cyano)methanimidate to provide intermediateXVI. Intermediate XVI is then protected and, if desired to form acompound of a preferred embodiment, alkylated with a suitably protectedbenzyl. The intermediate XVII can then be coupled to a suitablysubstituted phenyl boronic acid by Suzuki chemistry to provide theinstant compound.

Compounds of the instant invention wherein the A¹ (CR¹ ₂)_(n) A² (CR¹₂)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 14. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 1) provides the instant compound XX. If other R¹ substituents aredesired, the acetyl moiety can be manipulated as illustrated in theScheme.

Addition of various nucleophiles to an imidazolyl aldehyde may also beemployed to form a substituted alkyl linker between the biheteroaryl andthe preferred W (imidazolyl) as shown in Scheme 15. Thus abishalogenated five membered heteroaryl, such as 2,4-dibromothiophene,may undergo metal halogen exchange followed by reaction with a suitablysubstituted imidazolyl aldehyde and acteylation to form a regioisomericmixture of the acetyl intermediates. The halogenated regioisomericmixture may be chromatographically separated at this stage, ifconvenient. Suzuki coupling with a suitably substituted 6-memberedheteroaryl boronic acid affords the instant acetoxy compound, which canbe treated with lithium hydroxide to remove the acetyl group. Then,similar substituent manipulation as shown in Scheme 14 may be performedon a fully functionalized compound which incorporates an R² hydroxylmoiety. ##STR20## incorporated in the compounds of the instant inventionis represented by other than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other arylheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes, asshown in Scheme 16. The aldehydes can be prepared by standardprocedures, such as that described by O. P. Goel, U. Krolls, M. Stierand S. Kesten in Organic Syntheses, 1988, 67, 69-75, from theappropriate amino acid. Metal halogen exchange chemistry (Scheme 15) maybe employed when manipulating the aldehydes. Alternatively, Grignardchemistry may be utilized, as shown in Scheme 16. Thus, Suzuki couplingprovides, for example, the pyrrole containing biheteroaryl XXI. Reactionof the intermediate XXI with a Grignard reagent provides theN-pyrrylmagnesium derivative XXIa, which is then reacted with analdehyde to provide the C-alkylated instant compound XXII. The productXXII can be deoxygenated by methods known in the art, such as acatalytic hydrogention, then deprotected with trifluoroacetic acid inmethylene chloride to give the final compound XXIIa. The final productXXII may be isolated in the salt form, for example, as atrifluoroacetate, hydrochloride or acetate salt, among others. Theproduct diamine XXII can further be selectively protected to obtainXXIII, which can subsequently be reductively alkylated with a secondaldehyde to obtain XXIV. Removal of the protecting group, and conversionto cyclized products such as the dihydroimidazole XXV can beaccomplished by literature procedures.

Scheme 17 illustrates the use of in situ formation of a lithium anion ofa suitably substituted N-alkyl pyrrole to provide the C-alkylatedcompound of the instant invention.

If the arylheteroaryl subunit is reacted with an aldehyde which also hasa protected hydroxyl group, such as XXVI in Scheme 18, the protectinggroups can be subsequently removed to unmask the hydroxyl group (Schemes18, 19). The alcohol can be oxidized under standard conditions to e.g.an aldehyde, which can then be reacted with a variety of organometallicreagents such as Grignard reagents, to obtain secondary alcohols such asXXX. In addition, the fully deprotected amino alcohol XXXI can bereductively alkylated (under conditions described previously) with avariety of aldehydes to obtain secondary amines, such as XXXII (Scheme19), or tertiary amines.

The Boc protected amino alcohol XXVIII can also be utilized tosynthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 20).Treating XXVIII with 1,1'-sulfonyldiimidazole and sodium hydride in asolvent such as dimethylformamide led to the formation of aziridineXXXIII. The aziridine is reacted with a nucleophile, such as a thiol, inthe presence of base to yield the ring-opened product XXXIV.

In addition, the arylheteroaryl subunit can be reacted with aldehydesderived from amino acids such as O-alkylated tyrosines, according tostandard procedures, to obtain compounds such as XL, as shown in Scheme21. When R' is an aryl group, XL can first be hydrogenated to unmask thephenol, and the amine group deprotected with acid to produce XLI.Alternatively, the amine protecting group in XL can be removed, andO-alkylated phenolic amines such as XLII produced.

Schemes 22-25 illustrate syntheses of suitably substituted aldehydesuseful in the syntheses of the instant compounds wherein the variable Wis present as a pyridyl moiety. Similar synthetic strategies forpreparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art. ##STR21##

The instant compounds are useful as pharmaceutical agents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas activity (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) or byother mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545 (1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal,2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase)in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase to famesylatethe substrate, the chemical content of the assay mixtures may bedetermined by well known immunological, radiochemical or chromatographictechniques. Because the compounds of the instant invention are selectiveinhibitors of FPTase, absence or quantitative reduction of the amount ofsubstrate in the assay mixture without the compound of the instantinvention relative to the presence of the unchanged substrate in theassay containing the instant compound is indicative of the presence ofFPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain famesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 1 1-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl!ethyl}-4-phenyl-imidazolebishydrochloride salt

Step A: 1H-Imidazole-4-acetic acid methyl ester hydrochloride

A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6mmol) in methanol (100 mL) was saturated with gaseous hydrogen chloride.The resulting solution was allowed to stand at room temperature for 18hours. The solvent was evaporated in vacuo to afford the title compoundas a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 8.85(1H, s), 7.45(1H, s), 3.89(2H, s) and3.75(3H, s) ppm.

Step B: 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester

To a solution of the product from Step A (24.85 g, 0.141 mol) in DMF(115 mL) was added triethylamine (57.2 mL, 0.412 mol) andtriphenylmethyl bromide (55.3 g, 0.171 mol) and the suspension wasstirred for 24 hours. After this time, the reaction mixture was dilutedwith EtOAc and water. The organic phase was washed with sat. aq. NaHCO₃,dried, (Na₂ SO₄) and the solvent evaporated in vacuo. The residue waspurified by chromatography (Silica gel, 0-100% EtOAc in hexanes) toprovide the title compound as a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.35(1H, s), 7.31(9H, m), 7.22(6H, m),6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.

Step C: 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetic acid methyl ester

To a solution of the product from Step B (8.00 g, 20.9 mmol) inacetonitrile (70 mL) was added 4-cyanobenzyl bromide (4.10 g, 20.92mmol) and heated at 55° C. for 3 hours. The reaction was cooled to roomtemperature and the resulting imidazolium salt was collected byfiltration. The filtrate was heated at 55° C. for 18 hours. The reactionmixture was cooled to room temperature and evaporated in vacuo. To theresidue was added EtOAc (70 mL) and the resulting precipitate collectedby filtration. The precipitated imidazolium salts were combined,suspended in methanol (100 mL) and heated to reflux for 30 minutes.After this time, the solvent was removed in vacuo. The resulting residuewas suspended in EtOAc (75 mL) and the solid isolated by filtration andwashed with EtOAc. The solid was treated with sat. aq. NaHCO₃ solution(300 mL) and CH₂ Cl₂ (300 mL) and stirred at room temperature for 2hours. The organic layer was separated, dried, (MgSO₄) and evaporated invacuo to afford the title compound as a white solid.

¹ HNMR (CDCl₃, 400 MHz) δ 7.65(1H, d, J=8 Hz), 7.53(1H, s), 7.15(1H, d,J=8 Hz), 7.04(1 H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: 5- 1-(4-Cyanobenzyl)-1H-imidazolyl!ethanol

To a stirred solution of the ester from example step C, (1.50 g, 5.88mmol), in methanol (20 mL) at 0° C., was added sodium borohydride (1.00g, 26.3 mmol) portionwise over 5 minutes. The reaction was stirred at 0°C. for 1 hour and then at room temperature for 1 hour. The reaction wasquenched by the addition of sat. aq. NH₄ Cl solution and the methanolevaporated in vacuo. The residue was partitioned between EtOAc and sat.aq. NaHCO₃ solution and the organic extracts dried, (MgSO₄) andevaporated in vacuo. The residue was purified by chromatography (Silicagel, 4-10% methanol in CH₂ Cl₂) to afford the title compound as a whitesolid.

¹ H NMR (CDCl₃ 400 MHz) δ 7.64(2H, d, J=8.2 Hz), 7.57(1H, s), 7.11(2H,d, J=8.2 Hz), 6.97(1H, s), 5.23(2H, s), 3.79(2H, t, J=6.2 Hz), 2.66(2H,t, J=6.2 Hz) ppm.

Step E: 5-(1-(4-Cyanobenzyl)-imidazolyl)ethylmethanesulfonate

A solution of 5- 1-(4-cyanobenzyl)-1H-imidazolyl! ethanol (0.500 g, 2.20mmol) in CH₂ Cl₂ (6 mL) at 0° C. was treated with Hunig's base (0.460mL, 2.64 mmol) and methanesulfonyl chloride (0.204 mL, 2.64 mmol). After2 hours, the reaction was quenched by addition of saturated NaHCO₃solution (50 mL) and the mixture extracted with CH₂ Cl₂ (50 mL), dried,(MgSO₄) and the solvent evaporated in vacuo. The title compound was usedwithout further purification.

¹ H NMR (CDCl₃ 400 MHz) δ 7.69 (1H, s) 7.66(2H, d, J=8.2 Hz), 7.15 (2H,d, J=8.2 Hz), 7.04(1H, s), 5.24(2H, s), 4.31(2H, t, J=6.7 Hz), 2.96(3H,s), and 2.88(2H, t, J=6.6 Hz)ppm.

Step F: 1-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!ethyl}-4-phenyl-imidazolebis hydrochloride salt

To a suspension of sodium hydride (14.2 mg, 60% dispersion in mineraloil, 0.356 mmol) in DMF (0.30 mL) at 0° C. was added 4-phenylimidazole(48.8 mg, 0.339 mmol), and stirred for 20 minutes. A solution of themesylate from step E (100 mg, 0.339 mmol) in DMF (0.50 mL) was added tothe solution and stirring continued at 0° C. for 1 hour and then at roomtemperature for 16 hours. The reaction was quenched with sat. aq.ammonium chloride solution (0.10 mL), and the solvent evaporated invacuo. The residue was purified by chromatography (Silica gel, 2-5% NH₄OH: acetonitrile). The resulting material was converted to the HCl saltby treating an EtOAc solution of the imidazole with gaseous HCl andevaporation of the solvent in vacuo.

Anal. Calcd for C₂₂ H₁₉ N₅.2.00HCl.1.50H₂ O: C, 58.29; H, 5.34; N,15.45. Found: C, 58.24; H, 5.47; N, 15.48. FAB HRMS exact mass calcd forC₂₂ H₂₀ N₅ 354.171871 (MH⁺); found 354.171948. ¹ H NMR (CD₃ OD 400 MHz)δ 8.93 (1H, s), 8.75(1H, s), 7.86(1H, s), 7.76(2H, d, J=7.9 Hz),7.69(2H, d, 7.1 Hz), 7.65-7.35(6H, m), 5.61(2H, s) and 4.53(2H,m)ppm.

Example 21-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-4-phenylimidazole bishydrochloride salt

Step A: 1-Triphenylmethyl-4-(hydroxymethyl)imidazole

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260mmol) in dry DMF (250 mL) at room temperature was added triethylamine(90.6 mL, 650 mmol). A white solid precipitated from the solution.Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was addeddropwise. The reaction mixture was stirred for 20 hours, poured overice, filtered, and washed with ice water. The resulting product wasslurried with cold dioxane, filtered, and dried in vacuo to provide thetitled product as a white solid which was sufficiently pure for use inthe next step.

Step B: 1-Triphenylmethyl-4-(acetoxymethyl)imidazole

The alcohol from Step A (260 mmol, prepared above) was suspended inpyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was addeddropwise, and the reaction was stirred for 48 hours during which itbecame homogeneous. The solution was poured into EtOAc, washedsequentially with water, 5% aq. HCl solution, sat. aq. NaHCO₃, solution,and brine. The organic extracts were dried, (Na₂ SO₄), and concentratedin vacuo to provide the product as a white powder, which wassufficiently pure for use in the next reaction.

Step C: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide

A solution of the product from Step B (85.8 g, 225 mmol) and4-cyanobenzyl bromide (50.1 g, 232 mmol) in EtOAc (500 mL) was stirredat 60° C. for 20 hours, during which a pale yellow precipitate formed.The reaction was cooled to room temperature and filtered to provide thesolid imidazolium bromide salt. The filtrate was concentrated in vacuoto a volume (200 mL), heated at 60° C. for 2 hours, cooled to roomtemperature, and filtered. The filtrate was concentrated in vacuo to avolume (100 mL), heated at 60° C. for 2 hours, cooled to roomtemperature, and concentrated in vacuo to provide a pale yellow solid.All of the solid material was combined, dissolved in methanol (500 mL),and warmed to 60° C. After 2 hours, the solution was concentrated invacuo to provide a white solid which was triturated with hexane toremove soluble by products. Removal of residual solvents in vacuoprovided the titled product as a white solid which was used in the nextstep without further purification.

Step D: 1-(4-Cyanobenzyl)-5-(hydroxymethyl)imidazol

To a solution of the acetate from Step C (50.4 g, 150 mmol) in 3:1THF/water (1.5 L) at 0° C. was added lithium hydroxide monohydrate (18.9g, 450 mmol). After 1 hour, the reaction was concentrated in vacuo,diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO₃ andbrine. The solution was then dried (Na₂ SO₄), filtered, and concentratedin vacuo to provide the crude product as a pale yellow fluffy solidwhich was sufficiently pure for use in the next step without furtherpurification.

Step E: 1-(4-Cyanobenzyl)-5-(chloromethyl)imidazole

A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole (1.00 g, 4.70mmol), in thionyl chloride (5 mL), was stirred at 70° C. for 16 hours.The solvent was evaporated in vacuo and the resulting solid suspended inCH₂ Cl₂, collected by filtration and dried in vacuo. The material wassufficiently pure for use in the next step without further purification.

¹ H NMR (CD₃ OD 400 MHz) δ 9.06 (1H, s), 7.83(2H, d, J═8.0 Hz), 7.77(1H,s), 7.55(2H, d, J=8.0 Hz), 5.67(2H, s) and 4.78(2H, s) ppm.

Step F: 1-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!ethyl}-4-phenyl imidazolebis hydrochloride salt

To a solution of the chloride from step E (500 mg, 1.65 mmol) in DMF (10mL) at 0° C. was added sequentially, 4-phenyl-imidazole (238 mg, 1.65mmol) and sodium hydride (145 mg, 60% dispersion in mineral oil, 3.62mmol). Stirring was continued at 0° C. for 1 hour and then at roomtemperature for 16 hours. The reaction was quenched with water (50 mL),and extracted with CH₂ Cl₂. The organic extracts were dried, (MgSO₄),and the solvent evaporated in vacuo. The residue was purified bychromatography (Silica gel, 3-5% NH₄ OH: acetonitrile). The imidazolewas converted to the hydrochloride salt by treating an EtOAc solution ofthe resulting material with gasseous HCl and evaporation of the solventin vacuo.

Anal. Calcd for C₂₁ H₁₇ N₅.2.00HCl.1.75H₂ O.0.30EtOAc: C, 56.70; H,5.34; N, 14.89. Found: C, 56.71; H, 5.22; N, 14.91. ¹ H NMR (CD₃ OD 400MHz) δ 9.32(1H, d, J=1.4 Hz), 8.87(1H, s), 8.07(1H, s), 7.69(1H, d,J=1.6 Hz), 7.60-7.45(7H, m), 7.24(2H, d, J=8.6 Hz), 5.75(2H, s) and5.72(2H, s)ppm.

Example 31-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-4-(2-methyl)phenylimidazole bis hydrochloride salt

Step A: 4-(2-Methyl)phenyl imidazole

A solution of 1-(2-methyl)phenyl-2-bromoethanone (1.97 g, 9.24 mmol) informamide (12 mL), was heated at 215° C. for 2 hours. The reaction wascooled to room temperature and 0.2M aq. HCl (120 mL) was added and theresulting solid removed by filtration. The filtrate was treated withsat. aq. NH₄ OH to pH 10 and extracted with EtOAc . The organic extractswere washed with brine, dried, (MgSO₄) and evaporated in vacuo. Theresidue was purified by chromatography (Silica gel, EtOAc) to afford thetitle compound.

Step B: 1-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl!ethyl}-4-(2-methyl)phenyl)imidazolebis hydrochloride salt

The title compound was prepared using the protocol described in Example2, Step F using 4-(2-methyl)phenyl imidazole.

Anal. Calcd. for C₂₂ H₁₉ N₅.2.15HCl.1.75H₂ O. C, 57.03 H, 5.36N, 15.12.Found: C, 57.02; H, 5.35; N, 15.29. ¹ H NMR (CD₃ OD, 400MHz) δ 9.25(1H,s), 8.89(1H, s), 8.03(1H, s), 7.68(2H, d, J=8.2 Hz), 7.58(1H, d, J=1.6Hz), 7.45-7.25(6H, m), 5.76(2H, s), 5.73(2H, s) and 2.35(3H, s) ppm.

Example 4 1-(3-Phenyl-5-isoxazolylmethyl)-5-(4-cyanobenzyl) imidazolehydrochloride salt

Step A: 1-Trityl-4-(4-cyanobenzyl)-imidazole To a suspension ofactivated zinc dust (3.57 g, 54.98 mmol) in THF (50 mL) was addeddibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred for 45minutes under argon at 20° C. The suspension was cooled to 0° C. anda-bromo-p-toluinitrile (9.33 g, 47.6 mmol) in THF (100 mL) was addeddropwise over a period of 10 minutes. The reaction was then allowed tostir at 20° C. for 6 hours and bis(triphenylphosphine)Nickel 11 chloride(2.4 g, 3.64 mmol) and 4-iodotritylimidazole (15.95 g, 36.6 mmol) wereadded in one portion. The resulting mixture was stirred 16 hours at 20°C. and then quenched by addition of saturated NH₄ Cl solution (100 mL)and the mixture stirred for 2 hours. Saturated aq. NaHCO₃ solution wasadded to give a pH of 8 and the solution was extracted with EtOAc (2×250mL), dried, (MgSO₄) and the solvent evaporated in vacuo. The residue waschromatographed (Silica gel, 0-20% EtOAc in CH₂ Cl₂) to afford the titlecompound as a white solid.

¹ H NMR δ CDCl₃ (7.54 (2H, d, J=7.9 Hz), 7.38(1H, s), 7.36-7.29 (1H, m),7.15-7.09(6H, m), 6.58(1H, s), and 3.93(2H, s)ppm.

Step B: 1-(3-Phenyl-5-isoxazolylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

A suspension of 1-(bromomethyl)-3-phenylisoxazole (31.3mg, 0.13 mmol),1-trityl-4-(4-cyanobenzyl)-imidazole (60 mg, 0.13 mmol) in acetonitrile(0.20 mL) was stirred at 55° C. for 16 hours. The solvent was evaporatedin vacuo and the residue dissolved in methanol (5 mL) and stirred atreflux for 1 hour. The solvent was evaporated in vacuo and the residuepartitioned between CH₂ Cl₂, and aq. NaHCO₃. The organic extract wasdried, (MgSO₄) and the solvent evaporated in vacuo. The residue waspurified by chromatography (Silica gel, 0-3% MeOH in CH₂ C₂), andconverted to the hydrochloride salt by treatment with hydrochloric acidin EtOAc. Evaporation of the solvent in vacuo afforded the titlecompound.

Anal. Calcd. for C₂₁ H₁₆ N₄ O.1.00 HCl. C, 66.93 H, 4.55 N, 14.97.Found: C, 66.84; H, 4.39; N, 14.51. ¹ H NMR (CD₃ OD, 400MHz) δ 9.21(1H,s), 7.51(2H, m), 7.58(2H, d, J=8.0), 7.54-7.43(4H, m), 7.33(2H, d, J═8.0Hz), 6.62(1H, s), 5.70(2H, s) and 4.31(2H, s) ppm.

Example 5 1-(3-Phenyl-isoxazol-5-ylacetyl)-5-(4-cyanobenzyl) imidazolehydrochloride salt

The title compound was prepared using the protocol described in Example4, Step B using 5-(bromoacetyl)-3-phenyl isoxazole.

Anal. Calcd. for C₂₂ H₁₆ N₄ O₂. 2.55HCl.0.50H₂ O. C, 60.65 H, 4.50 N,12.41. Found: C, 60.72; H, 4.51; N, 12.16. ¹ H NMR (CD₃ OD, 400 MHz) 68.95(1H, d, J=1.5 Hz), 8.00-7.90(2H, m), 7.73(1H, s), 7.64(2H, d, J=8.4Hz), 7.58-7.50(3H, m), 7.48-7.40(3H, m), 5.85(2H, s), 4.23(2H, s) ppm.

Example 6 1-(4-Cyanobenzyl)-5-(4-Phenyl-thiazol-2-ylmethyl)imidazolehydrochloride salt

Step A: 4- 5-(Aminocarbonylmethyl)imidazol-1-ylmethyl!benzonitrile

To a 100 mL glass pressure vessel with a stirring bar was added1-(4-cyanobenzyl)-1H-imidazol-5-yl acetic acid methyl ester (6.00 g,23.5 mmol) and absolute ethanol (50 mL). This well stirred solution wascooled to -78° C. and 50 mL of anhydrous ammonia was condensed in. Thevessel was sealed and the mixture warmed to ambient temperature. Thissolution was stirred 24 hours at ambient temperature. The excess ammoniawas allowed to evaporate and the ethanol was removed in vacuo. The solidresidue was triturated with EtOAc and collected on a frit. This materialwas dried in vacuo to give the title compound as a white solid.

¹ H NMR (DMSO-d₆, 400 MHz) δ 3.25(s, 2H), 5.32(s, 2H), 6.88(s, 1H),6.96(s,1H), 7.24(d, j=8 Hz,2H), 7.42(s,1H), 7.68(s,1H), 7.83(d, j=8 Hz,2H).

Step B: 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!aminothiocarbonylmethyl

To a 50 mL round bottomed flask with a stirring bar, reflux condenserand an argon inlet was added 4-5-(aminocarbonylmethyl)imidazol-1-ylmethyl!benzonitrile (0.36 g, 1.49mmol), Lawesson's reagent (0.73 g, 1.8 mmol) and 1,4-dioxane (10 mL).This well stirred mixture was heated at 80° C. for 24 hours. The cooledreaction mixture was concentrated in vacuo and the residue waschromatographed (silica gel, 10% 2-propanol in ammonia saturated CHCl₃).The title compound was obtained as a yellow, crystalline solid.

¹ H NMR (DMSO-d₆, 400 MHz) 6 3.66(s, 2H), 5.41(s, 2H), 6.85(s, 1H),7.24(d, j=8 Hz,2H), 7.70(s,1H), 7.82(d, j=8 Hz, 2H), 9.21(s, 1H),9.56(s, 1H).

Step C: 1-(4-Cyanobenzyl)-5-(4-phenyl-thiazol-2-ylmethyl)imidazolehydrochloride salt

To a 25 mL round bottomed flask with a stirring bar reflux condenser andan argon inlet was added1-(4-Cyanobenzyl)-1H-imidazol-5-yl1aminothiocarbonylmethyl (0.12 g,0.468 mmol), dry THF (10 mL), and a-bromoacetophenone (0.098 g, 0.491mmol). This mixture was heated at 50° C. for 7 hours. The cooledreaction mixture was diluted with EtOAc and washed sucessively with aq.NaHCO₃ , water, and brine. Drying (MgSO₄), filtration and removal of thesolvent in vacuo gave a solid. This material was chromatographed (silicagel, 3% 2-propanol in ammonia saturated CHCl₃). The purified product wasconverted into the hydrochloride salt with 4M HCl in 1,4-dioxane. Thismaterial was triturated with EtAOc and collected on a frit. The productwas dried in vacuo at 50° C.

mp: 245°-247° C. (HCl salt). ¹ H NMR (CDCl₃, 400 MHz, free base) δ1.70(br s, 1H), 4.23(s, 2H), 5.27(s, 2H), 7.04(d, j═8 Hz, 2H),7.14(s,1H), 7.29(s, 1H), 7.35 (m,1H), 7.44 (m, 2H), 7.49(d, j=8 Hz, 2H),7.56(s, 1H) and 7.78 (d, j=8 Hz, 2H) ppm.

Example 71-(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazolehydrobromide salt

Step A: 1-(2-Methyl)phenyl-2-bromoethanone

To a 500 mL round bottomed flask with a stirring bar and an argon inletwas added CHCl₃ (200 mL), THF (100 mL), 2-methylacetophenone (10 mL,76.46 mmol), and pyridinium bromide perbromide (26.85 g, 84.11 mmol).This solution was stirred at ambient temperature for 24 hours. Thereaction mixture was washed with 5% aqueous HCl, H₂ O, and brine. Drying(MgSO₄), filtration and removal of the solvent in vacuo gave an oil.This material was vacuum distilled at 15 torr to give1-(2-methyl)phenyl-2-bromoethanone, bp: 143°-148° C. as a green oil.

¹ H NMR (CDCl₃, 400 MHz) δ 2.51(s, 3H), 4.41 (s, 2H), 7.22 (m, 2H), 7.41(m, 1H), 7.66 (d, j=7 Hz, 1H).

Step B:1-(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazolehydrobromide salt

To a 25 mL round bottomed flask with a stirring bar reflux condenser andan argon inlet was added1-(4-cyanobenzyl)-1H-imidazol-5-yl!aminothiocarbonylmethyl (0.15 g,0.585 mmol), dry THF (10 mL), and 1-(2-methyl)phenyl-2-bromoethanone(0.274 g, 1.28 mmol). This mixture was heated at 50° C. for 2.5 h. Thecooled reaction mixture was concentrated in vacuo. The material wastriturated with EtOAc and collected on a frit. The product was dried invacuo at 50° C.

mp: 215°-216° C. (HBr salt). ¹ H NMR (DMSO-d₆) δ 2.36(s, 3H), 4.53(s,2H), 5.63(s, 2H), 7.25(m, 3H), 7.34(d, j=8 Hz, 1H), 7.45(d, j=8 Hz, 1H),7.62 (s, 1H), 7.70 (br s, 2H), 7.72(d, j=8 Hz, 2H), 9.15(s, 1H).

Example 81-(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2-ylmethyl)imidazolehydrochloride salt

Step A: 1-(3-Chloro)phenyl-2-bromoethanone

To a 100 mL round bottomed flask with a stirring bar and an argon inletwas added 3-chloroacetophenone (0.60 g, 3.85 mmol), CHCl₃ (20 mL), andbenzyltrimethylammonium bromide perbromide (180 g, 4.62 mmol). Thissuspension stirred at ambient temperature for 48 hours. The reactionmixture was diluted with EtOAc and this solution was washed with H₂ Oand brine. Drying (MgSO₄), filtration and removal of the solvent gave anoil. This material was chromatographed (Silica gel, 5% EtOAc inhexanes). The title compound was obtained as an oil.

¹ H NMR (CDCl₃,400 MHz) δ 4.42(s, 2H), 7.47 (t, j=8 Hz, 1H), 7.58 (d,j=8 Hz, 1H), 7.86 (d, j=8 Hz, 1H) and 7.97 (s, 1H) ppm.

Step B:1-(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2-ylmethyl)imidazolehydrochloride salt

To a 50 mL round bottomed flask with a stirring bar, reflux condenserand an argon inlet, was added1-(4-cyanobenzyl)-1H-imidazol-5-yl!aminothiocarbonylmethyl (0.15 g,0.585 mmol), THF (10 mL), and 1-(3-chloro)phenyl-2-bromoethanone (0.18g, 0.77 mmol). This mixture was heated at 50° C. for 3 hours. The cooledmixture was concentrated in vacuo and the residue was partitionedbetween EtOAc and aq. NaHCO₃ solution. The layers were separated and theorganic phase was washed with brine, dried, (MgSO₄) filtered andconcentrated in vacuo. This material was chromatographed (Silica gel, 2%CH₃ OH in EtOAc). The main chromatographic product was repurified byliquid chromatogrphy (0.1% TFA in H₂ O:CH₃ CN--gradient 95:5 to 5:95) toprovide two compounds as TFA salts. The TFA salt material thus obtainedwas converted into the HCl salts with 4M HCl in 1,4-dioxane. The titlecompound, isolated as the major component, was triturated with EtOAc andcollected on a frit. The product was dried in vacuo at 50° C. mp:245°-246° C.

¹ H NMR (DMSO-d₆, free base) δ 4.56(s, 2H), 5.67(s, 2H), 7.32(d, j=8 Hz,2H), 7.43(m, 2H), 7.65(d, j=8 Hz, 2H), 7.74 (br s,1H), 7.80 (br s, 1H),8.11(s, 1H), 9.33(s, 1H).

The minor component was isolated: (3-{4-4-(3-chlorophenyl)-thiazol-2-yl!-3-H-imidazol-4-yl)acetonitrile,hydrochloride.

mp:219°-220° C. ¹ H NMR (DMSO-d₆) δ 4.18(s, 2H), 5.49(s, 2H), 7.43(d,j=8.3 Hz, 2H), 7.48(d, j=7.5 Hz, 2H), 7.63(s, 1H), 7.99(d, j=7.5 Hz,2H), 8.05(d, j=8.3 Hz, 2H), 8.35(s, 1H), 8.97(br s, 1H).

Example 91-(4-Cyanobenzyl)-5-(4-(naphth-2-yl)-thiazol-2-ylmethyl)imidazolehydrochloride salt

To a 35 mL round bottomed flask with a stirring bar, condenser and anargon inlet was added1-(4-cyanobenzyl)-1H-imidazol-5-yl!aminothiocarbonylmethyl (0.15 g,0.585 mmol), THF (10 mL), and 1-(2-naphthalenyl)-2-bromoethanone (0.175g, 0.70 mmol). The well stirred mixture was heated at 50° C. for 2hours. The mixture was cooled to room temperature and allowed to stirover night. The solvent was removed in vacuo and the residue waspartitioned between EtOAc and aq. NaHCO₃ solution. The layers wereseparated and the organic phase was washed with H₂ O and brine. Drying(MgSO₄), filtration and removal of the solvent in vacuo gave an oil.This material was chromatographed (Silica gel, 2% 2-propanol in ammoniasaturated CHCl₃). The product was converted into the hydrochloride saltwith 4M HCl in 1,4-dioxane. The HCl salt was triturated with EtOAc andcollected on a frit. The product was dried in vacuo at 50° C. for 24hours. mp: 245°-246° C.

¹ H NMR (DMSO-d₆, 400 MHz, free base)6 4.57(s, 2H), 5.68(s, 2H), 7.36(d,j=8 Hz, 2H), 7.52(m, 2H), 7.68(d, j=8 Hz, 2H), 7.74(br s, 1H), 7.96 (m,3H), 8.11(s, 1H), 8.35(s, 1H) and 9.22(s, 1H) ppm.

Example 101-((4-(2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt

Step A: 1-o-Tolyl-propan-1-one

To an oven dried 100 ml 3 neck flask equipped with septa, thermo probeand stirred bar was stirring a solution of o-tolunitrile (1 ml, 8.5mmol) in 40 ml dry THF at 0° C. To this cold, well stirred solution wasadded a solution of ethylmagnesium bromide (17 ml, 17 mmol) in THF viasyringe while keeping the temperature below 5° C. Removed ice bath andallowed the yellow solution to stir at ambient temperature for 24 h. Thereaction was cooled to 0° C. and quenched with a solution of saturatedNH₄ Cl (50 ml), extracted with 2× EtOAc and washed with H₂ O, brine,drying (MgSO₄), filtration and removal of solvent in vacuo to give acrude oil. This material was chromatographed (Silica gel, 3%EtOAc/Hexane) to affort the title product.

¹ H NMR (CDCl₃, 300 MHz) δ 1.17(t, 3H), 2.31(s, 3H), 2.6(q, 2H),7.15-7.26(m, 4H)

Step B: 2-Bromo-1-o-tolyl-propan-1-one

To a 50 ml round bottomed flask with stirring bar and an argon inlet wasadded CH₃ Cl (10 ml), THF (5 ml), 1-o-tolyl-propan-1-one (318 mg, 2.14mmol, and pyridium bromide perbromide (735 mg, 2.36 mmol). This solutionwas stirred at ambient temperature for 2 h. The reaction mixture waswashed with 5% aqueous HCl, H₂ O, and brine. Drying (MgSO₄), filtrationand removal of sovent in vacuo gave an oil. This material waschromatographed (Silica gel, 5% EtOAc/Hexane) to affort the titleproduct.

¹ H NMR (CDCl₃, 400 MHz) δ 1.88(d, J=6.7 Hz, 3H), 2.5(s, 3H), 5.20(q, IH), 7.25-7.29(m, 2H), 7.38(m, 1H), 7.61 (d, J=7.14 Hz, 1H).

Step C:1-((4-(2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

To a 100 mL round bottomed flask with a stirring bar, refluxed condenserand an argon inlet was added1-(4-cyanobenzyl)-1H-imidazol-5-yl!aminothiocarbonylmethyl (0.68, 2.65mmol), THF (30 mL), and 2-Bromo-1-o-tolyl-propan-1-one (1.2 g, 5.3mmol). The well stirred mixture was heated at 60° C. for 96 hours. Thecooled mixture was concentrated in vacuo and the residue was partitionedbetween EtOAc and aq. NaHCO₃ solution. The layers were separated and theorganic phase was washed with H₂ O and brine. Drying (MgSO₄), filtrationand removal of the solvent in vacuo gave an oil. This material waschromatographed (Silica gel, 2% 2-propanol in ammonia saturated CHCl₃).The main chromatographic product was repurified by liquid chromatogrphy(0.1% TFA in H₂ O:CH₃ CN--gradient 95:5 to 5:95) to provide twocompounds as TFA salts. The TFA salt material thus obtained wasconverted into the HCl salts with 4M HCl in 1,4-dioxane. The titlecompound, isolated as the major component, was triturated with ether andcollected on a frit. The product was dried in vacuo at 50° C.mp:108°-110° C.

¹ H NMR (DMSO-d₆, 400 MHz) δ 2.07(s, 3H), 2.19(s, 3H), 4.44(s, 2H),7.11(d, J=7.3 Hz, 1H), 7.23-7.30(m, 3H), 7.38(d,J=8.2 Hz, 2H), 7.70 (s,1H), 7.78(d, J=8.0 Hz, 2H), 9.28(br s, 1H).

Example 11 1-((4-(2-methylphenyl)thiazole-2-ylethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt

The title compound was prepared using the protocol described in example1 steps A-C, where step A was a standard reduction of urocanic acid andthen Fisher esterification to provide the methyl-ester in step C. Thetitle compound was prepared using the procedures described in example 8steps A and B.

¹ H NMR (CDCl₃, 400 MHz) δ 2.37(s,1H), 3.18(br s, 2H), 3.46(br s, 2H),5.71(br s,2H), 7.20(s,1H), 7.27-7.34(m, 4H), 7.38(d, J=6.95 Hz, 2H),7.49(d, J=7.14, 1H), 7.60(d, J=7.32, 2H) 9.69(br s, 1H). Anal. Calcd.for C₂₃ H₂₀ N₄ S.2.0HCl.1.50H₂ O. C, 57.03; H, 5.20; N, 11.57. Found: C,56.86; H, 4.99; N, 11.95.

Example 1012 In vitro inhibition of ras famesyl transferase

Assays of farnesyl-protein transferase.

Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIMand Ras-CAIL) were prepared as described by Schaber et al., J. Biol.Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800(1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively.Bovine FPTase was assayed in a volume of 100 μl containing 100 mMN-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH7.4, 5 mM MgCl₂, 5 mM dithiothreitol (DTT), 100 mM ³ H!-farnesyldiphosphate ( ³ H!-FPP; 740 CBq/mmol, New England Nuclear), 650 nMRas-CVLS and 10 μg/ml FPTase at 31° C. for 60 min. Reactions wereinitiated with FPTase and stopped with 1 ml of 1.0M HCL in ethanol.Precipitates were collected onto filter-mats using a TomTec Mach 11 cellharvester, washed with 100% ethanol, dried and counted in an LKB β-platecounter. The assay was linear with respect to both substrates, FPTaselevels and time; less than 10% of the ³ H!-FPP was utilized during thereaction period. Purified compounds were dissolved in 100% dimethylsulfoxide (DMSO) and were diluted 20-fold into the assay. Percentageinhibition is measured by the amount of incorporation of radioactivityin the presence of the test compound when compared to the amount ofincorporation in the absence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention described in the above Examples1-11 were tested for inhibitory activity against human FPTase by theassay described above and were found to have IC₅₀ of 50 μM.

Example 13 In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRatl or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemeted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl_(2/) 1 mM DTT/10mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCI) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 14 In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Ratl cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appro- priateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR22## wherein: a is N or C;from 0-4 ofb, c, d and e are independently N, NH, O and S, and the remaining b, c,d and e atoms are independently CH, provided that if a is C, then atleast one of b, c, d or e is independently N, NH, O or S; R¹ and R² areindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R³,R⁴ and R⁵ are independently selected from:a) hydrogen, b) unsubstitutedor substituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ C(O)O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁-C₆ alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, unsubstituted orsubstituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂,R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R^(6a), R^(6b), R^(6c), R^(6d) andR^(6e) on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e)is unsubstituted or substituted heterocycle, attachment of R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to Q is through a ring carbon; R⁷ isselected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl,heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:a) C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d)HO, e) ##STR23## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or h) C₁₋₄ perfluoroalkyl; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, cyanophenyl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹⁰ OC(O)NH--; provided that when R⁸ is heterocycle,attachment of R⁸ to V is through a ring carbon; R⁹ is independentlyselected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, Br, R¹¹ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byC₁ -C₆ perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; A¹ and A² are independentlyselected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --,--NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,providedthat V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ isa bond, n is 0 and A² is S(O)_(m) ; provided that when V is heterocycle,attachment of V to R⁸ and to A¹ is through a ring carbon; W is aheterocycle; X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷C(O)--, --C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--, --NR⁷ --, --S(O)₂N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --, provided that if a is N,then X is not O, --C(O)NR⁷ --, --C(O)O--, --C(O)NR⁷ C(O)--, --S(O)₂N(R¹⁰)-- or --NR⁷ --; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; r is 0 to 5,provided that r is 0 when V is hydrogen; and t is 0 or 1; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 of the formula A: ##STR24## wherein: a is N or C;from 0-4 of b,c, d and e are independently N, NH, O and S, and the remaining b, c, dand e atoms are independently CH, provided that if a is C, then at leastone of b, c, d or e is independently N, NH, O or S; R¹ is independentlyselected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁-C₆ alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³, R⁴ and R⁵ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; orany two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;provided that when R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) is unsubstituted or substitutedheterocycle, attachment of R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to Qis through a ring carbon; R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,heteroarylsulfonyl, unsubstituted or substituted with:a) C₁₋₄ alkoxy, b)aryl or heterocycle, c) halogen, d) HO, e) ##STR25## f) --SO₂ R¹¹ g)N(R¹⁰)₂ or h) C₁₋₄ perfluoroalkyl; R⁸ is independently selected from:a)hydrogen, b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl,R¹⁰ O--, R¹⁰ C(O)NR ¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment ofR⁸ to V is through a carbon; R⁹ is selected from:a) hydrogen, b) C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl; R¹¹ is independently selected from C₁ -C₆alkyl and aryl; R¹² is independently selected from hydrogen, C₁ -C₆alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl,C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that whenV is heterocycle, attachment of V to R⁸ and to A¹ is through a ringcarbon; W is a heterocycle selected from pyrrolidinyl, imidazolyl,imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl,triazolyl or isoquinolinyl; X is a bond, O, --C(═O)--, --CH═CH--,--C(O)NR⁷ --, --NR⁷ C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --or --S(═O)_(m) --; provided that if a is N, then X is not O, --C(O)NR⁷--,--S(O)₂ N(R¹⁰)--or --NR⁷ --; m is 0, 1 or 2; n is independently 0, 1,2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; r is 0to 5, provided that r is 0 when V is hydrogen;and t is 0 or 1; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1 of the formula B: ##STR26## wherein: a is N or C;from 0-4 of b,c, d and e are independently N, NH, O and S, and the remaining b, c, dand e atoms are independently CH, provided that if a is C, then at leastone of b, c, d or e is independently N, NH, O or S; R¹ is independentlyselected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁-C₆ alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³ and R⁴ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; orany two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent carbonatoms are combined to form a diradical selected from --CH═CH--CH═CH--,--CH═CH--CH₂ --, --(CH₂)₄ -- and --(CH₂)₃ --;provided that when R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) is unsubstituted or substitutedheterocycle, attachment of R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to Qis through a ring carbon; R⁸ is independently selected from:a) hydrogen,b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,andc) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to Vis through a ring carbon; R^(9a) and R^(9b) are independently hydrogen,C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰ is independently selectedfrom hydrogen, C₁ -C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; R¹² isindependently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁-C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substitutedheteroaralkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that whenV is heterocycle, attachment of V to R⁸ and to A¹ is through a ringcarbon; X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --,O or --C(═O)--; provided that if a is N, then X is not --C(O)NR¹⁰ --,--NR¹⁰ -- or O ; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; pis 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V ishydrogen; or a pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 1 of the formula C: ##STR27## wherein: a is N orC;from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl; R² is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R³ and R⁴ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--;provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) isunsubstituted or substituted heterocycle, attachment of R^(6a), R^(6b),R^(6c), R^(6d) or R^(6e) to Q is through a ring carbon; R⁸ isindependently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;providedthat when R⁸ is heterocycle, attachment of R⁸ to V is through a ringcarbon; R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; R¹² is independentlyselected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substitutedaralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, C₁ -C₆perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl,imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl,isoquinolinyl, triazolyl and thienyl, c) aryl, d) C₁ -C₂₀ alkyl whereinfrom 0 to 4 carbon atoms are replaced with a heteroatom selected from O,S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen ifA¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; provided that when V is heterocycle, attachment of V to R⁸and to A¹ is through a ring carbon; X is a bond, --CH═CH--, --C(O)NR¹⁰--, --NR¹⁰ C(O)--, --NR¹⁰ --, O or --C(═O)--;provided that if a is N,then X is not --C(O)NR¹⁰ --, --NR¹⁰ -- or O ; m is 0, 1 or 2; n isindependently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4, provided that p isnot 0 if X is a bond, --NR¹⁰ -- or O; and r is 0 to 5, provided that ris 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof.5. The compound according to claim 3 of the formula D: ##STR28##wherein: a is N or C;from 0-4 of b, c, d and e are independently N, NH,O and S, and the remaining b, c, d and e atoms are independently CH,provided that if a is C, then at least one of b, c, d or e isindependently N, NH, O or S; R¹ is independently selected from:hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R² is independentlyselected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, C₁ -C₆ alkyl and CF₃; R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R^(6a), R^(6b), R^(6c), R^(6d) andR^(6e) on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --; provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e)is unsubstituted or substituted heterocycle, attachment of R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to Q is through a ring carbon; R⁸ isindependently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, andc) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;providedthat when R⁸ is heterocycle, attachment of R⁸ to V is through a ringcarbon; R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ ormethyl; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; A¹ is selected from: a bond, --C(O)--, O,--N(R¹⁰)--, or S(O)_(m) ; X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰C(O)--, --NR¹⁰ --, O or --C(═O)--, provided that if a is N, then X isnot --C(O)NR¹⁰ --, --NR¹⁰ -- or O; n is 0 or 1; provided n is not 0 ifA¹ is a bond, O, --N(R¹⁰)--, or S(O)_(m) ; m is 0, 1 or 2; and p is 0,1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 4 of the formula E: ##STR29## wherein: a isN or C;from 0-4 of b, c, d and e are independently N, NH, O and S, andthe remaining b, c, d and e atoms are independently CH, provided that ifa is C, then at least one of b, c, d or e is independently N, NH, O orS; R¹ is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F,C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R² is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ C(O)--NR¹⁰ --; R⁴is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ; R^(6a), R^(6b),R^(6c), R^(6d) and R^(6e) are independently selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;provided that when R^(6a), R^(6b), R^(6c), R^(6d) orR^(6e) is unsubstituted or substituted heterocycle, attachment ofR^(6a), R^(6b), R^(6c), R^(6d) or R^(6e) to Q is through a ring carbon;R⁸ is independently selected from:a) hydrogen, b) aryl, substitutedaryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;providedthat when R⁸ is heterocycle, attachment of R⁸ to V is through a ringcarbon; R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ ormethyl; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl, 2,2,2-trifluoroethyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen,C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰C(O)--, --NR¹⁰ --, O or --C(═O)--;provided that if a is N, then X is not--C(O)NR¹⁰ --, --NR¹⁰ -- or O; n is 0 or 1; m is 0, 1 or 2; and p is 0,1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰ C(O)--,--NR¹⁰ -- or O; or a pharmaceutically acceptable salt thereof.
 7. Thecompound according to claim 5 of the formula F: ##STR30## wherein: a isN or C;from 0-4 of b, c, d and e are independently N, NH, O and S, andthe remaining b, c, d and e atoms are independently CH, provided that ifa is C, then at least one of b, c, d or e is independently N, NH, O orS; R¹ is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl or C₁-C₆ alkyl; R² is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F, c) C₁ -C₆alkyl unsubstituted or substituted by aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R³ is selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)R¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, CH₃ and CF₃ ;R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S (O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R^(6a), R^(6b), R^(6c), R^(6d) andR^(6e) on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --; provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e)is unsubstituted or substituted heterocycle, attachment of R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to Q is through a ring carbon; R^(9a)and R^(9b) are independently hydrogen, halogen, CF₃ or methyl; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl; R¹¹ is independently selected from C₁ -C₆alkyl and aryl; R¹² is independently selected from hydrogen, C₁ -C₆alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl,C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰C(O)--, O or --C(═O)--;provided that if a is N, then X is not --C(O)NR¹⁰-- or O; m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4; or a pharmaceuticallyacceptable salt thereof.
 8. The compound according to claim 6 of theformula G: ##STR31## wherein: a is C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that at least one of b, c, d or e isindependently N, NH, O or S; R¹ is independently selected from:hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R²is independently selected from:a) hydrogen, b) aryl, heterocycle or C₃-C₁₀ cycloalkyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R³ is selected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁴ is selected from H, halogen, CH₃ and CF₃ ;R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selectedfrom:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; or any two of R^(6a), R^(6b), R^(6c), R^(6d) andR^(6e) on adjacent carbon atoms are combined to form a diradicalselected from --CH═CH--CH═CH--, --CH═CH--CH₂ --, --(CH₂)₄ -- and--(CH₂)₃ --;provided that when R^(6a), R^(6b), R^(6c), R^(6d) or R^(6e)is unsubstituted or substituted heterocycle, attachment of R^(6a),R^(6b), R^(6c), R^(6d) or R^(6e) to Q is through a ring carbon; R^(9a)and R^(9b) are independently hydrogen, halogen, CF₃ or methyl; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl,2,2,2-trifluoroethyl and aryl; R¹¹ is independently selected from C₁ -C₆alkyl and aryl; R¹² is independently selected from hydrogen, C₁ -C₆alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl,C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; p1 A¹ is selected from: a bond, --C(O)--, O,--N(R¹⁰)--, or S(O)_(m) ; m is 0, 1 or 2; and n is 0 or 1; or thepharmaceutically acceptable salts thereof.
 9. A compound which inhibitsfarnesyl-protein transferase which is:1-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl!ethyl}-4-phenyl-imidazole1-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-4-(2-methyl)phenylimidazole 1-(3-Phenyl-5-isoxazolylmethyl)-5-(4-cyanobenzyl) imidazole1-(3-Phenyl-isoxazol-5-ylacetyl)-5-(4-cyanobenzyl) imidazole1-(4-Cyanobenzyl)-5-(4-Phenyl-thiazol-2-ylmethyl)imidazole1-(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazole1-(4-Cyanobenzyl)-5-(4-(3 -chlorophenyl)-thiazol-2-ylmethyl)imidazole or1-(4-Cyanobenzyl)-5-(4-(naphth-2-yl)-thiazol-2-ylmethyl)imidazole1-((4-(2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5-(4-cyanobenzyl)imidazole or 1-((4-(2-methylphenyl)thiazole-2-ylethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
 10. Thecompound according to claim 9 which is: ##STR32## or a pharmaceuticallyacceptable salt thereof.
 11. The compound according to claim 9 which is:##STR33## or a pharmaceutically acceptable salt thereof.
 12. Thecompound according to claim 9 which is: ##STR34## or a pharmaceuticallyacceptable salt or optical isomer thereof.
 13. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 1. 14. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 3. 15. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 4. 16. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 9. 17. A method for inhibitingfamesyl-protein transferase which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 13. 18. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 14. 19. A method forinhibiting famesyl-protein transferase which comprises administering toa mammal in need thereof a therapeutically effective amount of acomposition of claim
 15. 20. A method for inhibiting famesyl-proteintransferase which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 16. 21. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 13. 22. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim
 14. 23. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 15. 24. A method for treatingcancer which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 16. 25. Amethod for treating neurofibromin benign proliferative disorder whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 13. 26. A method for treatingblindness related to retinal vascularization which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 13. 27. A method for treatinginfections from hepatitis delta and related viruses which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 13. 28. A method for preventingrestenosis which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 13. 29. Amethod for treating polycystic kidney disease which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 14. 30. A pharmaceutical compositionmade by combining the compound of claim 1 and a pharmaceuticallyacceptable carrier.
 31. A process for making a pharmaceuticalcomposition comprising combining a compound of claim 1 and apharmaceutically acceptable carrier.